PROJECT II ? DIABETES, CEREBRAL VASCULAR DYSFUNCTION AND COGNITIVE IMPAIRMENTS PROJECT SUMMARY/ABSTRACT Diabetes mellitus (DM) is one of the leading risk factors for cerebrovascular disease (CVD) and cognitive impairment, especially at the late stage with mild hypertension, but the underlying mechanisms have not been fully elucidated. Dementia is one of the major causes of disability, and the 5th leading cause of death in the elderly in the US. The annual cost for treating dementia is $159 billion, and is projected to rise to $511 billion by 2040. There is an urgent need to understand the mechanisms involved and for development of new therapeutic strategies to delay the onset and progression of these devastating diseases. Mounting evidence suggests that DM is associated with impaired endothelial function and neurovascular coupling, and elevated myogenic tone and reactivity at an early stage. The enhanced myogenic tone and activity in DM decline with age, however, it is to be determined whether CBF autoregulation is impaired in vivo and if it plays a role in the development of dementia in hypertensive DM. This proposal builds upon our preliminary data indicating that the myogenic response and CBF autoregulation are impaired in response to elevated cerebral perfusion pressure in our novel diabetic rat models. Following development of mild hypertension, DM rats exhibit BBB leakage, inflammation, vascular remodeling, neurodegeneration and cognitive dysfunction. Importantly, forced dilatation of middle cerebral artery (MCA) and CBF autoregulatory breakthrough occurring at lower pressure are only observed in older DM rats with long standing hyperglycemia and after they have developed mild hypertension. We also observed that the neurodegeneration is associated with elevated expression of beta amyloid (A? 1-42) and pTau (S416) in the brain in mild hypertensive DM rats, suggesting that Alzheimer-like neuronal cell death pathways are also activated. The enhanced expression of GFAP and IL-1? in hypertensive DM rats indicate that glial activation and inflammation may play a role in linking aging, diabetes and cognitive deficits. In translational studies, we found that cognitive impairment in elderly participants in a largely diabetic ARIC-NCS population may be associated with impaired CBF autoregulation. This proposal will use our novel non-obese types 1 and 2 DM rat models, which do not exhibit severe lipid and other metabolic derangements normally associated with DM, to investigate whether impaired myogenic response and CBF autoregulation contribute to cognitive impairment, and whether the synergistic effects of DM and hypertension promote development of cognitive deficits. We will also use luseogliflozin to normalize plasma glucose levels by inhibition of renal sodium-glucose co-transporter 2 (SGLT2) without altering blood pressure in our DM models, as we previously reported, to determine the role of hyperglycemia in cerebral vascular dysfunction and dementia. This proposal will address one of the significant gaps in this field by investigating whether chronic hyperglycemia, especially in association with hypertension, causes impairment of CBF autoregulation and dementia using our novel diabetic rat models.